Process for producing a purified prostaglandin derivative

Abstract

An alkene (1) is added to cyclopentenone (2) under the action of an alkyl lithium and an organic copper reagent to form an adduct, said adduct is reacted with e.g. a carboxylic anhydride (4) to obtain a prostaglandin derivative (6), which is then treated with a nitrogen-containing compound such as 2,2'-bipyridyl to efficiently remove the organic copper reagent used in the synthesis and by-products derived from said reagent, to obtain a purified prostaglandin derivative (6) having a high purity:

What is claimed is:  
     
       1. A process for producing a purified prostaglandin derivative, which comprises adding an alkene represented by the following formula (1) to a cyclopentenone represented by the following formula (2) under the action of an alkyllithium and an organic copper reagent to form an adduct, reacting said adduct with a carboxylic acid halide represented by the following formula (3), a carboxylic anhydride represented by the following formula (4) or a mixed carboxylic anhydride represented by the following formula (5) to obtain a reaction product containing a prostaglandin derivative represented by the following formula 6, and then treating said reaction product with a nitrogen-containing compound:                    
       wherein 
       R 1  is an alkanoyl group or an alkanoyl group containing a hereto atom in the alkyl group moiety,  
       R 2  is an alkyl group or an alkyl group containing a hereto atom,  
       each of R 3  and R 4  which are independent of each other, is a protecting group for a hydroxyl group or a hydrogen atom,  
       R 5  is an alkyl group, a substituted alkyl group, a cycloalkyl group, a substituted cycloalkyl group, an alkenyl group or an alkynyl group,  
       R 6  is an alkanoyl group or an alkanoyl group containing a hereto atom in an alkyl group moiety, and is different from R 1 ,  
       Q is an ethylene group or a vinylene group,  
       X 1  is an iodine atom or a trialkyltin group,  
       X 2  is a halogen atom, and  
       wherein the nitrogen-containing compound is selected from the group consisting of  
       (a) an organic carboxylic acid amide compound,  
       (b) an organic thiourea compound,  
       (c) an organic phosphorous triamide compound,  
       (d) an organic phosphoric triamide compounds, and  
       (e) an organic amine compound selected from the group consisting of trimethylamine, triethylamine, triisopropylamine, tributylamine, trioctylamine, cyclohexylamine, pyrrolidine, piperidine, N-methylcyclohexylamine, aniline, N-methylaniline, and N,N-dimethylaniline.  
     
     
       2. The process according to  claim 1 , wherein a deprotecting reaction is carried out after the treatment with the nitrogen-containing compound, to obtain the prostaglandin derivative of the formula (6) wherein at least one of R 3  and R 4  is a hydrogen atom, and wherein the amount of the nitrogen-containing compound is from 1 to 100 times the molar quantity of the organic copper reactant. 
     
     
       3. The process according to  claim 1 , wherein the aromatic heterocyclic compound having a nitrogen atom as a hetero atom, is a compound represented by the formula (7):                    
       wherein 
       each of R 7  and R 8  which are independent of each other is a hydrogen atom or an alkyl group,  
       each of Y 1  and Y 2  which are independent of each other, is a nitrogen atom or CH, provided that Y 1  to which R 7  is bonded is C, and Y 2  to which R 8  is bonded is C,  
       n is an integer of from 0 to 5, and  
       m is an integer of from 1 to 3.  
     
     
       4. The process according to  claim 1  or  2 , wherein the means of treating the reaction product with a nitrogen-containing compound is a method of mixing the reaction product with the nitrogen-containing compound, followed by stirring. 
     
     
       5. The process according to  claim 1  or  2 , wherein the temperature during the treatment of the reaction product with a nitrogen-containing compound is from −20° C. to room temperature. 
     
     
       6. The process according to  claim 1  or  2 , wherein the purified prostaglandin derivative contains substantially from 0 ppm to 100 ppm of copper based on the prostaglandin derivative. 
     
     
       7. The process according to  claim 1  or  2 , wherein the prostaglandin derivative represented by the formula 6 is butyl 9-butanoyloxy-11α, 15S-dihydroxyprosta-8,13E-dien-1-oate. 
     
     
       8. The process according to  claim 1 , wherein the nitrogen-containing compound is the organic carboxylic acid amide compound. 
     
     
       9. The process according to  claim 1 , wherein the nitrogen-containing compound is the organic thiourea compound. 
     
     
       10. The process according to  claim 1 , wherein the nitrogen-containing compound is the organic phosphorous triamide compound. 
     
     
       11. The process according to  claim 1 , wherein the nitrogen-containing compound is the organic phosphoric triamide compound. 
     
     
       12. The process according to  claim 1 , wherein the nitrogen-containing compound is the organic amine compound. 
     
     
       13. The process according to  claim 1 , wherein the alkyl lithium is t-butyl lithium. 
     
     
       14. The process according to  claim 1 , wherein the organic copper reagent is a trialkylphosphine-copper iodide (I) complex. 
     
     
       15. The process according to  claim 1 , wherein the nitrogen-containing compound is thiourea, 1,3-dimethyl-2-thiourea, or 1,1,3,3-tetramethyl-2-thiourea. 
     
     
       16. The process according to  claim 1 , wherein the nitrogen-containing compound is hexamethylphosphorous triamide or hexaethylphosphorous triamide. 
     
     
       17. The process according to  claim 1 , wherein the nitrogen-containing compound is hexamethylphosphoric triamide or hexaethylphosphoric triamide. 
     
     
       18. The method of  claim 1 , wherein the amount of the nitrogen-containing compound is from 1 to 100 times the molar quantity of the organic copper reactant. 
     
     
       19. The method of  claim 8 , wherein the amount of the nitrogen-containing compound is from 1 to 100 times the molar quantity of the organic copper reactant. 
     
     
       20. The method of  claim 9 , wherein the amount of the nitrogen-containing compound is from 1 to 100 times the molar quantity of the organic copper reactant. 
     
     
       21. The method of  claim 10 , wherein the amount of the nitrogen-containing compound is from 1 to 100 times the molar quantity of the organic copper reactant. 
     
     
       22. The method of  claim 11 , wherein the amount of the nitrogen-containing compound is from 1 to 100 times the molar quantity of the organic copper reactant. 
     
     
       23. The method of  claim 12 , wherein the amount of the nitrogen-containing compound is from 1 to 100 times the molar quantity of the organic copper reactant.